Derivatives of 1,2,4-benzothiadiazine-4-carboxaldehyde-1,1-dioxide

ABSTRACT

The present invention pertains to hypotensive agents of the formula WHEREIN X may be halogen, lower alkyl, trifluoromethyl or nitro; Y may be lower alkyl or lower alkene of at least three carbon atoms or -CHO; and R may be hydrogen, lower alkyl, lower cycloalkyl or aralkyl.

United States Patent Yale i541 DERIVATIVES 0F 1,2,4- BENZOTHIADIAZlNE-4- CARBOXALDEHYDE-1,1-DIOXIDE [72] Inventor: Harry Louis Yale, New Brunswick,

J.- 9 29 H r a [73] Assignee: E. L. Squibb & Sons, Inc., Princeton,

[22] Filed: Feb. 16, 1970 [21] Appl. No.: 11,906

[52] US. Cl. ..260/243 D, 424/246 [5 1] Int. Cl. ..C07d 93/32 [58] Field of Search ..260/243 D [56] References Cited UNITED STATES PATENTS 3,290,302 12/1966 Eloy ..260/243 D 3,318,879 5/1967 Wei et al ..260/243 D 3,379,735 4/1968 Sturm et al. ..260/243 D 3,344,139 9/1967 Wei et al ..260/243 D [451 Sept. 12, 1972 Primary Examiner-Nicholas S. Rizzo Attomey-Lawrence S. Levinson, Merle J. Smith, Donald J. Perrella and Burton Rodney [5 7] ABSTRACT The present invention pertains to hypotensive agents of the formula S02 NH Irlll Y wherein X may be halogem. lower alkyl,

trifluoromethyl or nitro; Y may be lower alkyl or lower alkene of at least three carbon atoms or -CHO; and R may be hydrogen, lower alkyl, lower cycloalkyl or aralkyl.

6 Claims, No Drawings DERIVATIVES OF l,2,4-BENZOTIIIADIAZINE-4- CARBOXALDEIIYDE- l l -DIOXIDE OBJECTS OF THE INVENTION It is an object of the present invention to provide new hypotensive agents and method for their preparation. Another object isto provide compounds which are effective. hypotensive agents'at relatively low dosages. A further object is to provide hypotensive agents which have prolonged effectiveness. These'and other objects of the present invention will be apparent from the following description.

SUMMARY OF THE INVENTION It has now been found .that compounds of. the formula are effective'hypotensive agents having prolongedeffeet at low dosage levels. In the formula above, X may be halogen F, Cl, Br or 1), lower alkyl of up to five carbon atoms (including branched as well as straight chain radicals), trifluoromethyl or nitro; Y may be lower alkyl of up to eight carbon atoms, or lower alkene of from three to eight carbon atoms (including branched as well as straight chain radicals, or CHO; and R may belower alkyl or cycloalkyl, each of up to eight carbon atoms, or aralkyl of up to carbon atoms, or hydrogen.

DETAILED DESCRIPTION Inthe compounds of the present invention, the substituent X includes in addition to halogen and nitro the following alkyl radicals: methyl, ethyl, n-propyl, ipropyl, n-butyLi-butyl, n-pentyl, Z-methyI-n-butyl, or neopentyl. The substituent Y may be any of the foregoing alkyl radicals and in addition also includes the following: n-hexyl, Z-methy-l-ri-pentyl, 3-methyl-n-pentyl, 2,2-dimethyl-n-butyl, 2,3-dimethyl-n-butyl, n-heptyl, 2- methylm-hexyl, 3-methyl-n-hexyl, 2,2-dimethyl-n-pentyl, 2,3-dimethyl-n-pentyl, 2,4-dimethyl-n-pentyl, 3,3- dimethyl-n-pentyl, 3-ethyl-n-pentyl, 2,2,3-trimethylbutane, n-octyl, Z-methyI-n-heptyl, 3-methyl-n-heptyl, 4- methyl-n-heptyl, 2,3-dimethyl-n-hexyl, 2,4-dimethyl-nhexyl, 2,5-do,etju;-n-hexyl, 2,2-dimethyl-n-hexyl, 3,3- dimethyl-n-hexyl, Z-ethyl-n-hexyl, 3-ethyl-n-hexyl, 2,2,3trimethyl-n-pentyl, 2,2,4-trimethyl-n-pentyl, 2,3,3-trimethyl-n-pentyl, 2,3,4-trimethyl-n-pentyl, 2- ethyl-3-methyl-n-pentyl, Z-methyI-S-ethyI-n-pentyl, and 2,2,3,B-tetramethyl-n-butyl. The substituent Y may also be a monounsaturated alkene corresponding to any of the foregoing alkyl radicals having from three to eight carbon atoms, specific examples of which are given above, or a cycloalkyl radical of up to eight carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopentyl, cycloheptyl, cyclooctyl, and methyl cycloheptyl, or an aralkyl radical 'of up to 10 carbon atoms, for example, benzyl, phenethyl, isopropylphenyl, 3-phenylpropyl and isopropylbenzyl.

The compounds described herein and the physiologically acceptable salts thereof are useful hypotensive agents and are useful in reducing high blood pressure. They may be used, for example, in a manner similar to guanethidine. As to the salts, those coming within the purview of this invention-include the acid-addition salts of. those compounds containing a basic group particularly the nontoxic acid-addition salts and the nontoxic quaternary ammonium salts. These salts frequently provide convenient means for separating the product from the reaction mixture in which it isproduced or from the solvent in which it is extracted in view of their insolubility invarious media. Thus the product may be precipitated in the form of an insoluble salt and converted,by conventional techniques, to the free base or to another soluble or insoluble salt as desired.

Such salts are easily prepared by methods known to the art. The base is reacted with either the calculated amount of organic or inorganic acid in aqueous miscible solvents, such as acetone or ethanol, with isolation of the salt by concentration and cooling or an excess of the acid in aqueous immiscible solvent, such as ethyl ether or chloroform, with the desired salt separating directly. Exemplary of such organic salts are those with acetic, oxalic, tartaric, maleic, fumaric, citric, ascorbic, pamoic, succinic, salicylic, bis-methylenesalicylic, benzoic, nicotinic, methylsulfonic, ethanesulfonic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzene sulfonic, camphorsulfonic, methanesulfonic, theophylline and theophylline acetic acids as well as with the 8-halotheophyllines, for example, 8- chlorotheophylline and 8-bromotheophylline. Exemplary of such inorganic salts are those with hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, phosphoric and nitric acids.

The quaternary ammonium salts include those formed with alkyl halides (e.g., methyl chloride, isobutyl bromide, dodecyl chloride and cetyl iodide), benzyl halides (e.g., benzyl chloride) and dilower alkyl aulfates (e.g., dimethyl sulfate). Of course these salts may also be prepared by the classical method of double decomposition of appropriate salts which is well known to the art.

I A compound of the invention or a physiologically acceptable salt thereof may be compounded according to accepted pharmaceutical practice in oral dosage forms such' as tablets, capsules, elixirs or powders or parenterally in an injectable form in a sterile vehicle prepared according to conventional pharmaceutical practice. The dosage level may vary from about 1 mg/kg to about 50 mg/kg.

Liquid oral dosage fomis may be prepared by dissolving the hypotensive agent in a suitable solvent, e.g., propylene glycol. Oral tablets may be prepared by incorporating the hypotensive agent into suitable pharmaceutical carriers. injectable forms may be prepared by incorporating the hypotensive agent in a sterile vehicle, e.g., propylene glycol, according to conventional practice.

The compounds of the invention produce gradual hypotension beginning a few minutes after dosing and yielding a moderate hypotension, i.e., a fall in blood pressure of about 20 percent or greater about three When Y is lower alkyl, or lower alkene of at least three carbon atoms, the compounds of the present invention are prepared according to the following reac- The X-substituted aniline hydrochloride salt I is converted to the N-acetyl derivative II by means of acetic anhydride. Compound III is formed by reaction of II with a Y-halide (chloride, bromide or iodide) under non-aqueous basic conditions at temperatures of from about 30 to about 80C. Compound III is hydrolyzed under reflux conditions with aqueous base or aqueous alcoholic base to yield Compound IV. Treatment of Compound IV with chlorosulfonic acid in tetrachloroethane at elevated temperatures (90150 C) in the presence of a small amount of NaCl yields Compound V. The latter is converted to Compound VI by means of thionyl chloride in the presence of. chlorosulfonic acid. Reaction of Compound VI with aqueous ammonia at elevated temperatures (80100 C) yields Compound VII. Reaction of VII with an aldehyde in the presence of hydrogen ion yields the final Compound VIII.

When Y is -CI-IO, the compounds of the present invention are prepared according to the following reaction sequence:

The X-substituted-2-nitrophenylsulfonamide IX is converted to the corresponding 2-hydroxyamino derivative X by hydrogenation in the presence of Pd catalyst. Hydrogenation of the latter in the presence of Pd catalyst at elevated temperatures (from about 50C to about 60C) yields the corresponding 2-amino derivative XI. Alternatively, Compound XI may be Ilal) ITCOCH3 mic acid yields the final product XIII.

Compound XI may also be prepared according to the following reaction sequence:

ClSOaII Compound XI is prepared starting from m-X-substituted aniline XIV and converting the latter to the corresponding sulfonic acid XV by reaction with chlorosulfonic acid in tetrachloroethane at elevated temperatures (90l50C) in the presence of a small amount of NaCl. Reaction of XV with thionyl chloride in the presence of chlorosulfonic acid yields the sulfonyI chloride derivative XVI. Reaction of the latter with aqueous ammonia at elevated temperatures (l00 C) yields Compound XI.

The following examples illustrate the present invention without, however, limiting the same thereto. All temperatures are expressed in degrees Centigrade.

EXAMPLE 1 o2,aa-Trifluoro-m-acetotoluidide To a vigorously stirred solution of 16l .0 g. of a,a,atrifluoro-m-toluidine in ml. of concentrated hydrochloric acid and I I. of water, at room temperature, is added, in one portion, l02.0 g. of acetic anhydrid'e. The acetyl derivative separates rapidly, is filtered, and dried to give 158.4 g. of a,a,a-trifluoro-macetotoluidide, m.p. about -97.

EXAMPLE 2 N-Ethyl-a,a,a-trifluoro-mfacetotoluidide TheN ethyl derivative, 135.5 g'., 500 ml. of 95 per-' cent ethanol, and 50 ml. of concentrated hydrochloric acid are refluxed for 8 hours and the alcohol is distilled. The residue is treated with an excess of 40 percent aqueous sodium hydroxide and the liberated oil ex-' tracted with ether. The ether extracts are dried, concentrated, and the residue distilled to give 720 g. of N- ethyl a,a,a-trifluoro-m-toluidine, b.p. about. 82 (4 mm.), n 1.4770.

EXAMPLE 4 2-(Ethylamino)-a,a,a-trifluoro-p-toluenesulfonic acid To 232 of N-ethyl-a,a,a-trifluoro-m-toluidine in 320 ml. of tetrachloroethane, is added, with cooling, g. of chlorosulfonic acid, dropwise, then 8.4 g. of sodium chloride. The mixture is heated slowly to reflux, maintained at reflux for 1 hour, cooled, and poured on ice. The solid which separates is filtered to give 12 g. of crude fonic acid, m.p. about 198-200 dec.; recrystallization from n-propyl alcohol gives 6.0 g. of pure acid, m.p. about 2l02l2 dec.

EXAMPLE 5 2-(Ethylamino)-a,a,a trifluoro-p-toluenesulfonyl chloride To ml. of chlorosulfonic acid at 0 is added, in portions, the above 6 g. of acid. The mixture is heated at 150 (oil bath temperature), kept at 150 for 3 hours, cooled to room temperature, 10 ml. of purified thionyl chloride added dropwise, and the mixture warmed carefully by means of a steam bath, heated for 1 hour on the steam bath, and poured on ice. The precipitated material is filtered and washed with a little water to give the title compound.

EXAMPLE 6 2-(Ethylamino)-a,a,a-trifluoro-p-toluenesulfonamide The precipitate from Example 5 is heated on the steam bath for 1 hour with 100 ml. of concentrated aqueous ammonia. The solid in the cooled reaction mixture is filtered, dried and extracted with 100 ml. of boiling benzene. The hot benzene solution is decanted and concentrated to dryness to give 0.35 g. of solid; recrystallization from 20 percent isopropyl alcohol-80 percent water gives 2-(ethylamino)-a,a,a-trifluoro-ptoluenesulfonamide, m.p. about l84-l 86.

EXAMPLE 7 3,4-Dihydro-4-ethyl-6-(trifluoromethyl l ,2,4- benzothiadiazinel l -dioxide 2-Ethylamino-a,a,a trifluoro-p-toluenesulfonamide 5.43 g., 1.28 g. of 37 percent of formalin solution, 50 ml. of 95 percent ethanol, and 2.5 ml. of aqueous 10 percent hydrochloric acid are heated under reflux for 2 hours and the solution concentrated to dryness. The

residual solid is recrystallized from water to give the title compound.

EXAMPLE 8 4-Allyl-6-chloro-3-methyl-1 ,2,4-benzothiadiazine-1 ,1 I dioxide Substituting m-chloroaniline for a,a,a-trifluoro-mtoluidine in Example 1, allyl chloride for the ethyl iodide inExample 2, and acetaldehyde'for the formalin in Example 7, and following the procedures of Examples l-7, the title product is formed.

EXAMPLE? 6Bromo-3-cyclopentyl-4-methyl-1 ,2,4- benzothiadiazine- 1 1 -dioxide Substituting m-bromoaniline for a,a,a-trifluoro-mtoluidine in Example 1, methyl bromide for the ethyl iodide in Example 2, and cyclopentanecarboxaldehyde (in the form of the acetal) for the formalin in Example 7, and following the procedures of Examples 1-7, the title product is formed.

EXAMPLE 10 3-Cyclohexyl-4-ethyl-6-fluoro-l ,2,4-benzothiadiazine- 1,1-dioxide Substituting m-fluoroaniline for 01,01,01-

trifluoroaniline in Example 1, and cyclohexanecarboxaldehyde (in the form of the acetal) for the formalin in Example 7, and following the procedure of Examples l-7, the title product is formed.

EXAMPLE ll 6-Methyl-3-phenethyl-4-propyl-1 ,2 ,4- benzothiadiazine-1 1 -dioxide Substituting m-toluidine for a,a,a-trifluoroaniline in Example 1, propyl chloride for the ethyl iodide in Example 2, and phenethylcarboxaldehyde (in the form of the acetal) for the formalin in Example 7, and following the procedure of Examples l-7, the title product is formed.

EXAMPLE 12 2-Nitro-a,a,a-trifiuoro-p-toluenesulfonamide A suspension of 367 g. of bis(2-nitro-a,a,a-trifluorop-tolyl)disulfide in 1,800 ml. of 90 percent acetic acid is diffused with gaseous chlorine at 3540 for 6 hours.

The clear solution which forms is concentrated in vacuo from a hot water bath, the residue is treated with 500 ml. of toluene, and the toluene solution, containing the sulfonyl chloride is added dropwise at room temperature to 500 ml. of aqueous ammonia (d 0.9). The solution is heated on the steam bath for 1 hour to give crude title product; this is extracted with 400 ml. of 20 percent aqueous sodium hydroxide and filtered, and the filtrate treated with excess 20 percent aqueous hydrochloric acid. The solid is filtered, washed with cold water, and recrystallized from water to give 362 g.

of the title compound: m.p. about 169-170; )t f p. (e) 276 (sh) (16,000) 266 16,500).

EXAMPLE 13 I 2-(Hydroxyamino)-q,a,a-trifiuoro-ptoluenesulfonamide Two identical experiments, each involving 30.0 g. of the compound formed in Example 12, 5.0 g. of 5 percent Pd-C, and 300 ml. of absolute ethanol are shaken at 20-25 under 50 psi of hydrogen, approximately 0.5 hours is required for the uptake of 0.22 mol. Work-up of the combined runs gives 51.0 g. the title compound; colorless: m.p. about 184-l 85 dec after recrystallization from water; A My. (6) 313 (3,100), 247 (8,200), 213 (23,300). The compound is soluble in dilute aqueous sodium hydroxide forming an orangeyellow solution; acidification gives a colorless solution from which unchanged title compound precipitates; a test of the compound with aqueous ferric chloride is negative.

EXAMPLE 14 2-Amino-a,a,a-trifluoro-p-toluenesulfonamide A. By hydrogenation of 2-nitro-a,a,a-trifluoro-ptoluenesulfonamide-Two identical reaction mixtures as in the above experiment are hydrogenated at 5060 under 50 psi of hydrogen; approximately 3.5 hours are required for the absorption of 0.33 mol. The two runs are combined and worked up to give 54.0 g. of colorless title compound, m.p. about 148149 after recrystallization from water; A Mu (e) 320 (4,200), 247 (10,000), 213 (24,100). The compound is soluble in dilute aqueous sodium hydroxide forming a colorless solution; acidification precipitates the unchanged compound.

B. By hydrogenation of 2-(hydroxyamino)-a,a,atrifluoro-p-toluenesulfonamide-A solution of 25.6 g. (0.1 mol.) of the compound formed in Example 13, 5.0 g. of 5 percent Pd-C, and 300 ml. of absolute ethanol is heated to 50-60 and shaken under 50 psi of hydrogen. Again, ca. 3 hours are required for the theoretical uptake of hydrogen to occur. Work-up as above gives 21.3 g. of title compound, m.p. about 148-l49 after recrystallization from water.

EXAMPLE l5 3 ,4-Dihydro-6-trifluoromethyl- 1 ,2,4-benzothiadiazine- 1,1-dioxide 0.01 M01. of the final compound of the preceding example, 0.01 mol. of 37 percent aqueous formaldehyde,

1.0 ml. of 10 percent aqueous HCl, and 50 ml. of 95 percent ethanol are heated under reflux for 3 hours and concentrated to dryness in vacuo. After recrystallization from water the title compound is obtained: m.p. about l63-165; k mu (6) 327 (35,000). 253 (12,500), 213 (22,300).

EXAMPLE l6 3,4-Dihydro-6-(trifluoromethyl )-l ,2,4- benzothiadiazine-4-carboxaldehyde-l l -dioxide EXAMPLE 17 3 ,4-Dihydro-3-benzyl-6-iodo-1 ,2,4-benzothiadiazine- 4-carboxaldehyde-1 1 -dioxide Substituting m-iodoaniline for the N-ethyl-a,a,atrifluoro-m-toluidine in Example 4, and following the procedures of Examples 4-6, 15 and 16, the title compound is obtained.

EXAMPLE 18 3,4-Dihydro-6-nitro-1,2,4-benzothiadiazine-4- carboxaldehyde-l ,l-dioxide Substituting m-nitraniline for the N-ethyl-a,a,atrifluoro-m-toluidine in Example 4, and following the procedures of Examples 4-6, 15 and 16, the title compound is obtained.

EXAMPLE 19 Oral Liquid l-lypotcnsive agent of Example 7 20 grams Propylene glycol, enough to make 5.0 liters The hypotensive agent is dissolved in the propylene glycol, brought up to final volume and packaged in amber glass bottles with tight fitting caps. Each 5 ml. contains 20 mg of the active compound. Before swallowing, 5 ml. are diluted in 4 oz of water or fruit juice.

EXAMPLE 20 Intramuscular Injection l-lypotensive agent of Example 7 SOgms. Methyl paraben, U.S.P. 1.0 gm. Propyl paraben, U.S.P. 0.1 gm. Propylene glycol, to make 1.0 Liters 9 from light.

The preparation is packaged in multiple-dose vials. Each ml provides 50 mg of the drug and is intended for intramuscular injection.

The lactose and acacia are mixed and granulated with the starch paste by first forming a damp mixture, comminut ng, drying and oscillating. The drug substance, the corn starch and the stearic acid are mixed and passed through a fine screen, mixed with the lactose granulation and compressed into tablets. Each tablet weighs 158 mg and contains 20 mg of drug.

While general methods have been given for the preapration of the compounds of the present invention, and specific illustrations of these methods have been given in the preceding examples, it is to be understood that reaction conditions and reactants may be varied in accordance with the knowledge of those skilled in the art. What is claimed is:

l. A compound of the formula wherein X is halogen, alkyl of up to five carbon atoms, trifluoromethyl or nitro, and R is hydrogen, alkyl or cycloalkyl of up to eight carbon atoms, or arylalkyl of up to 10 carbon atoms, provided that when X is trifluoromethyl, R is not hydrogen.

2. A physiologically acceptable salt of a compound of claim 1.

3. A compound of claim 1 having the name 3,4- dihydro-6-( trifluoromethyl l ,2,4-benzothiadiazine-4- carboxaldehydel l -dioxide.

4. A compound of claim 1 having the name 3,4- dihydro-3 -benzyl-6-iodo-1 ,2,4-benzothiadiazine-4-carboxaldehydel 1 -dioxide.

5. A compound of claim 1 having the name 3,4- dihydro-6-nitro-l ,2,4-benzothiadiazine-4-carboxaldehyde-l l -dioxide.

6. A process for preparing a compound of claim 1 which comprises reacting with formic acid a compound of the formula where X and R are as defined in claim 8. 

2. A physiologically acceptable salt of a compound of claim
 1. 3. A compound of claim 1 having the name 3,4-dihydro-6-(trifluoromethyl)-1,2,4-benzothiadiazine-4-carboxaldehyde- 1,1-dioxide.
 4. A compound of claim 1 having the name 3,4-dihydro-3-benzyl-6-iodo-1,2,4-benzothiadiazine-4-carboxaldehyde-1,1 -dioxide.
 5. A compound of claim 1 having the name 3,4-dihydro-6-nitro-1, 2,4-benzothiadiazine-4-carboxaldehyde-1,1-dioxide.
 6. A process for preparing a compound of claim 1 which comprises reacting with formic acid a compound of the formula where X and R are as defined in claim
 8. 